Substituted bis-acridines and related compounds as CCR5 receptor ligands, anti-inflammatory agents and anti-viral agents

ABSTRACT

This invention relates to substituted bis-acridines and related compounds which are ligands, in particular, antagonists of the CCR5 receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune disease such as multiple sclerosis, and inflammatory bowel disease, all in mammals, by the use of substituted bis-acridines and related compounds which are CCR5 receptor antagonists. Also, since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor ligands may be useful in the treatment of HIV infection.

FIELD OF THE INVENTION

[0001] This invention relates to substituted bis-acridines and relatedcompounds which are ligands, agonists or antagonists, of the CCchemokine receptor CC-CKR5 now designated as CCR5 (Nature Medicine 1996,2, 1174-8). In addition, this invention relates to the treatment andprevention of disease states mediated by CCR5.

BACKGROUND OF THE INVENTION

[0002] T cells are not only key regulators of the immune response toinfectious agents but are believed critical for the initiation andmaintenance of the inflammatory reaction in a variety of chronicdiseases. Increased numbers or enhanced activation state of T cells,especially CD4+T cells, have been demonstrated in the synovium ofindividuals with rheumatoid arthritis (M. J. Elliott and R. N. Maini,Int. Arch Alleryv Immnunol. 104: 112-1125, 1994), in the bronchialmucosa of asthmatics (C. J. Corrigan and A. B. Kay, Immunol. Today 13:501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H.F. McFarland, Crit. Rev. Clin. Lab. Sci. 32: 121-182, 1995), inpsoriatic lesions (J. L. Jones, J. Berth-Jone, A. Fletcher and P. E.Hutchinson, J. Pathol. 174: 77-82, 1994) and in the fatty streaks ofatherosclerosis (R. Ross, Annu. Rev. Phvsiol. 57: 791-804, 1995).

[0003] T cells, as well as other inflammatory cells, will migrate intotissues in response to the production of a variety chemotactic factors.Among these factors are a superfamily of 8-12 kDa proteins known as thechemokines. These proteins share structural features such as thepresence of 3-4 conserved cysteine residues. RANTES, which stands forRegulated upon Activation Normal T cell Expressed and Secreted, is a 8kDa protein member of CC branch of the chemokine family. These proteinsrecruit and activate immune and inflammatory cells through aninteraction with G-protein coupled receptors. The CC branch is definedby the absence of an intervening amino acid residue between the firsttwo cysteine residues and members of this family predominately elicitthe migration of mononuclear cells, eosinophils and basophils (M.Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994; andJ. J. Oppenheim, C. O. C. Zachariae, N. Mukaida, and K. Matsushima,Annu. Rev. Immunol. 9: 617-648, 1991).

[0004] RANTES potently produces chemotaxis of T cells, basophils,eosinophili; monocytes and mast cells. RANTES was originally identifiedas gene product induced late after antigen activation of T-cells (T. J.Schall, J. Jongstra, B. J. Dyer, J. Jorgensen, et al., J. Immunol.141:1018-1025, 1988), however, RANTES has been shown to be synthesizedand secreted by a diverse group of cells that include epithelial andendothelial cells (C. Stellato, L. A. Beck, G. A. Gorgone, D. Proud, etal., J. Immunol. 155: 410-418, 1995; and A. Marfaing-Koka, O. Devergne,G. Gorgone, A. Portier, et al., J. Immunol. 154: 1870-1878, 1994),synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick, T. J.Schall, et al., J. Biol. Chem. 268: 5834-5839, 1993) and dermalfibroblasts (M. Sticherling, M. Kupper, F. Koltrowitz, E. Bornscheuer,et al., J. Invest. Derrnatol. 105: 585-591. 1995), mesangial cells (G.Wolf, S. Aberle, F. Thaiss, et al., Kidney Int. 44: 795-804, 1994) andplatelets (Y. Koameyoshi, A. Dorschner, A. I. Mallet, E. Christophers,et al., J. Exp. Med. 176: 587-592, 1992). In these cells RANTES MnRNA israpidly upregulated in response to IL-1 or TNFa. Although RANTES mRNA isnot usually detected in normal tissues (J. M. Pattison, P. J. Nelson,and A. M. Krensky, Clin. Immunother. 4: 1-8, 1995), increased MRNA orprotein has been found in diseases characterized by a mononuclearinfiltrate. For example, RANTES mRNA was visualized using in situhybridization in renal allografts undergoing rejection (J. M. Pattison,P. J. Nelson, and A. M. Krensky, Clin. Immunother. 4: 1-8, 1995; and K.C. Nadeau, H. Azuma and N. I. Tilney, Proc. Natl. Acad. USA 92:8729-8733, 1995) in the skin of atopic dermatitis patients afterexposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng, M. Humbert, etal., J. Exp. Med. 181: 2153-2159, 1995), and in endothelial cells ofcoronary arteries undergoing accelerated atherosclerosis after cardiactransplant (J. M. Pattison, P. J. Nelson, and A. M. Krensky, Clin.Immunother. 4: 1-8, 1995). Further, increased immnunoreactive proteinfor RANTES has been detected in bronchoalveolar lavage fluid (R. Alam,J. York, M. Boyers, et al., Am. J. Resp. Crit. Care Med. 149: A951,1994) and sputum from asthmatic individuals (C. M. Gelder, P. S. Thomas,D. H. Yates, I. M. Adcock, et al., Thorax 50: 1033-1037, 1995).

[0005] Several receptors have been identified that bind RANTES. Inparticular, CCR5, when expressed in either HEK 293 cells or CHO cells,binds RANTES. This receptor is expressed in T-cells and in monocytes andmacrophages, immune/inflammatory cells which are important in themaintenance of a chronic inflammatory reaction. Pharmacologicalcharacterization of CCR5 indicates similarities to the RANTES bindingsite observed on isolated T cells. Therefore, antagonism of RANTES'action on CCR5, as well as antagonism of other natural ligands of CCR5,should inhibit the recruitment of T cells into inflammatory lesions andprovide a novel therapeutic approach for the treatment of atopic andautoimmune disorders.

[0006] Since T cells express CCR5, selective receptor ligands of CCR5,particularly antagonists, are likely to provide beneficial effects indiseases including, but not limited to, asthma and atopic disorders (forexample, atopic dermatitis and allergies), rheumatoid arthritis,atherosclerosis, psoriasis, autoimmune diseases such as multiplesclerosis, and inflammatory bowel disease, all in mammals, preferablyhumans. Also since CCR5 is a co-receptor for the entry of HIV intocells, selective receptor ligands may be useful in the treatment of HIVinfection.

[0007] A subset of compounds included in formula (I) have been reportedto have intercalating activity (J. Med. Chem. 1978, 21, 868-74; Biochem.Phannacol. 1977, 26, 275-8; and J. Med. Chem. 1978, 21, 658-68),mutagenic activity (Mutat. Res. 1990, 232, 33743, and Biochem. J. 1985,226, 175-82), antitumor activity (Biochem. Pharmacol. 1985, 34, 2123-8),antibacterial, antitubercular, and antileprotic activity (Chem. Pharm.Bull. 1972, 20, 206-8), and anti-acetylcholinesterase activity (Anal.Spectrosc. Libr. 1995, 6, 281-311).

[0008] Surprisingly, it has now been discovered that this class ofnon-peptide compounds, in particular substituted bis-acridines andrelated compounds of formula (I), function as CCR5 receptor ligands,agonists or antagonists, and therefore, have utility in the treatment ofdisease states wherein inhibition of CCR5 receptor mechanisms isindicated for prevention or therapeutic treatment.

SUMMARY OF THE INVENTION

[0009] In one aspect, the present invention is to a method of treatingCCR5 mediated disease states, including, but not limited to, asthma andatopic disorders (for example, atopic dermatitis and allergies),rheumatoid arthritis, atherosclerosis, psoriasis, autoimmnune diseasessuch as multiple sclerosis, inflammatory bowel disease, and HIVinfection, all in mamnmals, preferably humans, comprising administeringto such mammal in need thereof, an effective amount of a substitutedbis-acridine or related compound of formula (I), or pharmaceuticallyactive salts thereof:

[0010] wherein:

[0011] X are independently one or more of H, optionally substituted C₁₋₆alkyl, C₃₋₇ cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄alkyl, CH₂NR′₂, CH₂OR′, CN,COR′, CONR′₂, CO₂R′, CF₃, N(R′)₂, NR′COR′, NR′CONR′R′, NR′CO₂R″,NR′SO₂R″, NO₂, OR′, S(O)₀₋₂R″, S(O)₀₋₂CF₃, or halo;

[0012] R′ is H, optionally substituted C₁₋₆alkyl,C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl;

[0013] R″ is C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl;

[0014] D and D′ are independently CX or N;

[0015] V and V′ are independently C(R)₂, NR₁, O, or S(O)₀₋₂;

[0016] R₁ are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl,Ar-C₀₋₄alkyl, —C(O)CF₃, —C(O)R′, or —SO₂R″, or, when V and V′ are —NR₁,the two R₁ groups taken together may be (C(R)₂)₂₋₃ to form aheterocyclic ring of five to nine members;

[0017] n is 0, 1, 2or 3; and

[0018] R are independently H, C₁₋₆alkyC₃₋₇cycloalkyl-C₀₋₄alkyl orAr-C₀₋₄alkyl, or, when V and V′ are independently NR¹, O or S(O)₀₋₂, anytwo R taken together may be (C(R)₂)₂₋₄ to form a carbocyclic ring ofthree to eight members.

[0019] In another aspect, the present invention is to a genus of novelcompounds of formula (I), or pharmaceutically active salts thereof, saidcompounds which are also useful in treating the above-mentionedCCR5-mediated disease states:

[0020] wherein:

[0021] X are independently one or more of H, optionally substitutedC₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄alkyl, CH₂NR′₂, CH₂OR′, CN,COR′, CONR′₂, CO₂R′, CF₃, N(R′)₂, NR′COR′, NR′CONR′R′, NR′CO₂R″,NR′SO₂R″, NO₂, OR′, S(O)₀₋₂R″, S(O)₀₋₂CF₃, or halo;

[0022] R′ is H, optionally substituted C₁₋₆alkyl,C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl;

[0023] R″ is C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl;

[0024] D and D′ are independently CX or N;

[0025] V and V′ are independently C(R)₂, NR₁, O, or S(O)₀₋₂;

[0026] R₁ are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl,Ar-C₀₋₄alkyl, —C(O)CF₃, —C(O)R′, or —SO₂R″, or, when V and V′ are —NR₁,the two R₁ groups taken together may be (C(R)₂)₂₋₃ to form aheterocyclic ring of five to nine members;

[0027] n is 0, 1, 2 or 3; and

[0028] R are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl orAr-C₀₋₄alkyl, or, when V and V′ are independently NR¹, O or S(O)₀₋₂, anytwo R taken together may be (C(R)₂)₂₋₄ to form a carbocyclic ring ofthree to eight members, with the proviso that the compound of formula(I) is not 9,9′-(1,3-propanediyl)bis-acridine;9,9′-(1,5-pentanediyl)bis-acridine; N,N′-di-9-acridinyl-1,2-ethanediamine; N,N′-bis(4-ethyl-9-acridinyl)-1,2-ethanediamine;N,N′-bis(3-methoxy-9-acridinyl)-1,2-ethanediarine;N,N′-bis(4-butoxy-9-acridinyl)-1,2-ethanediarnine;N,N′-bis(6-chioro-2-methoxy-9-acridinyl)-I,2-ethanediamine;trans-N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-I,2-cyclohexanediamine;9,9′-(1,4-piperazinediyl)bis[6-chloro-2-methoxy-acridine];N,N′-di-9-acridinyl-1,2-propanediamine; N,N′-di-9-acridinyl-1,3-propanediamine; N,N′-bis(1-nitro-9-acridinyl)-1,3-propanediamine;N,N′-bis(6-chloro-2-niethoxy-9-acridinyl)-1,3-propanediarnine;N,N′-bis(6-chloro-2-blethoxy-9-acridinyl)-2,2-methyl-1,3-propanediarnine; N,N′-bis(6-chloro-2-fluoro-9-acridinyl)-1,3-propanediamine; N,N′-di-9-acridinyl- 1 ,4-butanediamirne;N,N′-bis(4-ethyl-9-acridinyl)- 1,4-butanediarnine; N,N′-bis( 1-nitro-9-acridinyl)- 1,4-butanediamine;N,N′-bis(3-methoxy-9-acridinyl)-1,4-butanediamine;N,N′-bis(4-propoxy-9-acridinyl)-1,4-butanediarmine;N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,4-butanediarnine;N,N′-bis(3,6-dichloro-9-acridinyl)- 1,4-butanediamine;6-chloro-N-[2-[(6-chloro-2-methoxy-9-acridinyl)thio]ethyl]-2-methoxy-9-acridinamine;9,9′-[1,2-ethanediylbis(thio)jbis-acridine;9,9′-[1,2-ethanediylbis(thio)]bis-3-acridinarniine;9,9′-[1,3-propanediylbis(thio)]bis-acridine;9,9′-[1,4-butanediylbis(thio)]bis-acridine; 9,9′-[1,4-butanediylbis(thio)]bis-1-acridinamine;9,9′-[1,4-butanediylbis(thio)]bis-3-acridinamine;9,9′-[1,4-butanediylbis(thio)]bis4-acridinamine;9,9′-[methylenebis(oxy)]bis-anthracene;9,9′-[methylenebis(oxy)]bis[10-methoxy-anthracenel;9,9′-[methylenebis(oxy)]bis[10-propoxy-anthracene];9,9′-[methylenebis(oxy)]bis[10-(2-methoxyethoxy)-anthracene];9,9′-[1,2-ethanediylbis(oxy)]bis-anthracene;9,9′-(1,3-propanediyl)bis-anthracene;9,9′-(1,4-butanediyl)bis-anthracene;9,9′-(1,4-butanediyl)bis[10(chloromethyl)-anthracene;9-[3-(9-anthracenyloxy)propyl]anthracene;9,9′-(1,5-pentanediyl)bis-anthracene;9,9′-(1,5-pentanediyl)bis[10-(chioromethyl)-anthracene; and9,9′-(1,6-hexanediyl)bis-anthracene.

[0029] In yet another aspect, the present invention is to pharmaceuticalcompositions comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier therefor. In particular, the pharmaceuticalcompositions of the present invention are used for treatingCCR5-mediated disease states, including, but not limited to, asthma andatopic disorders (for example, atopic dermatitis and allergies),rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseasessuch as multiple sclerosis, inflammatory bowel disease, and HIVinfection.

DETAILED DESCRIPTION OF THE INVENTION

[0030] It has now been discovered that substituted bis-acridines andrelated compounds of formula (I) are CCR5 receptor ligands. It has alsonow been discovered that selective inhibition of CCR5 receptormechanisms by treatment with the receptor ligands of formula (I), or apharmaceutically acceptable salt thereof, represents a novel therapeuticand preventative approach to the treatment of a variety of diseasestates, including, but not limited to, asthma and atopic disorders (forexample, atopic dermatitis and allergies), rheumatoid arthritis,atherosclerosis, psoriasis, autoimmune diseases such as multiplesclerosis, inflammatory bowel disease, and HIV infection, all inmammals, preferably humans.

[0031] The term “alkyl” is used herein at all occurrences to mean astraight or branched chain radical of 1 to 6 carbon atoms, unless thechain length is limited thereto, including, but not limited to methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,and the like.

[0032] The term “cycloalkyl” is used herein at all occurrences to meancyclic radicals, preferably of 3 to 7 carbons, including but not limitedto cyclopropyl, cyclopentyl, cyclohexyl, and the like.

[0033] The terms “halo” or “halogen” are used interchangeably herein atall occurrences to mean radicals derived from the elements chlorine,fluorine, iodine and bromine.

[0034] The terms “heteroring” or “heterocyclic ring” is used herein atall occurrences to mean a saturated or wholly or partially unsaturated5-, 6-, 7-, 8- or 9-membered ring system which contains one or moreheteroatoms selected from the group consisting of N, O, or S; such as,but not limited to, pyrrolidine, piperidine, piperazine, morpholine,imidazolidine or pyrazolidine.

[0035] The terms “aryl” or “Ar-” are used herein at all occurrences tomean substituted and unsubstituted aromatic ring(s) or ring systemswhich may include bi- or tri-cyclic systems. Representative examplesinclude, but are not limited to, phenyl, benzyl, and naphthyl.

[0036] The term “optionally substituted” is used herein at alloccurrences to mean that the moiety may or may not be substituted withone or more functional groups including —OCH₃, —N(R′)₂ and —CO₂R″. Itwill be understood that the optional substituents are selectedindependently from one another.

[0037] It will be understood that the substituent(s) X may be at anyopen position on the aromatic rings of formula (I) to which thesubstituent is attached. In addition, it will be understood that theremay be more than one substituent X in any given compound of formula (I),and that if there is more than one substituent X, that substituent maybe the same or different.

[0038] The “term CCR5 mediated disease state” is used herein at alloccurrences to mean any disease state which is mediated (or modulated)by CCR5.

[0039] Suitably, pharmaceutically acceptable salts of formula (1)include, but are not limited to, salts with inorganic acids such ashydrochloride, sulfate, phosphate, diphosphate, hydrobromide, andnitrate, or salts with an organic acid such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, palmitate, salicylate, andstearate. In addition, pharmaceutically acceptable salts of compounds offormula (1) may also be formed with a pharmaceutically acceptablecation, for instance, if a substituent group comprises a carboxy moiety.Suitable pharmaceutically acceptable cations are well known to thoseskilled in the art and include alkaline, alkaline earth, ammonium andquaternary ammonium cations.

[0040] For the compounds of formula (I) various embodiments are asfollows.

[0041] X is suitably independently one or more of H, optionallysubstituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄-alkyl, CH₂NR′₂,CH₂OR′, CN, COR′, CONR′₂, CO₂R′, CF₃, NR′₂, NR′COR′, NR′CONR′R′,NR′CO₂R″, NR′SO₂R″, NO₂, OR′, S(O)₀₋₂R″, S(O)₀₋₂CF₃, or halo. X ispreferably 2-OR′ and 6-Cl.

[0042] R′ is suitably H, optionally substituted C₁₋₆alkyl,C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl. R′ is preferably H oroptionally substituted C₁₋₆alkyl, more preferably CH₃, neopentyl, ort-butoxycarbonylmethyl.

[0043] R″ is suitably C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl orAr-C₀₋₄alkyl. R″ is preferably C₁₋₆allkyl.

[0044] D and D′ are suitably independently CX or N. D and D′ arepreferably N.

[0045] V and V′ are suitably independently C(R)₂, NR¹, O, or S(O)₀₋₂. Vand V′ are preferably NR¹.

[0046] R¹ are suitably independently H or C₁₋₆alkyl,C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄-alkyl, —C(O)CF₃, —C(O)R′, —SO₂R″, or,when V and V′ are —NR¹ the two R¹ groups taken together may be(C(R)₂)₂₋₃ to form a heterocyclic ring of five to nine members. R¹ ispreferably H or one of R¹ is —CO(CF₃).

[0047] Variable n is suitably 0, 1, 2 or 3. It will be understood thatwhen V is NR¹ and V′ is NR¹, O or S, n can be 0, 1, 2, or 3, except thatthis invention does not include compounds that are understood to beunstable when n is 0. Variable n is preferably 1.

[0048] R are suitably independently H, C₁₋₆alkyl,C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl, or, when V and V′ areindependently NR¹, O or S(O)₀₋₂, any two R taken together may be(C(R)₂)₂₋₄ to form a carbocyclic ring of three to eight members. R ispreferably H.

[0049] Among the preferred compounds of the invention are the followingcompounds:

[0050] N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1,2-ethanediaminebis(trifluoroactate);

[0051] N,N′-di-9-acridinyl-1,2-ethanediamine bis(trifluoroactate);

[0052] N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1,3-propanediaminebis(trifluoroactate);

[0053]9,9′-(1,4-piperazinediyl)bis[6-chloro-2-methoxy-acridine]bis(trifluoroacetate);

[0054]N-(6-chloro-2-methoxy-9-acridinyl)-N-(6-chloro-2-hydroxy-9-acridinyl)-1,2-ethanediamninebis(trifluoroacetate);

[0055] N,N′-bis(6-chloro-2-hydroxy-9-acridinyl)- 1 ,2-ethanediaminebis(trifluoroactate);

[0056]N-[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyl]-N-(6-chloro-2-hydroxy-9-acridinyl]-1,2-ethanediaminebis(trifluoroactate);

[0057]N-[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyl)-N-(6-chloro-2-methoxy-9-acridinyl]-1,2-ethanediaminebis(trifluoroactate);

[0058] N,N′-bis[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyl]- 1,2-ethanediamine bis(trifluoroactate);

[0059] N,N′-Bis[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyi] -1,2-ethanediarnine bis(trifluoroactate);

[0060]N-[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyl]-N-(6-chloro-2-hydroxy-9-acridinyl)-1,2-ethanediamine bis(trifluoroactate);

[0061]N-[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyl]-N-(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediaminebis(trifluoroactate);

[0062] N,N′-bis[(6-chloro-2-carboxymethoxy-9-acridinyl)- 1,2-ethanediamine bis(trifluoroactate);

[0063]N-[6-chloro-2-(2-dimethylarino)ethoxy-9-acridinyl]-N-(6-chloro-2-hydroxy-9-acridinyl]-1,2-ethanediamrinebis(trifluoroactate);

[0064] N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N,N′-dimethyl-1,2-ethanediamine bis(trifluoroactate);

[0065]N,N′-bis(6-cloro-2-methoxy-9-acridinyl)-N,N′-bis(trifluoromethylcarbonyl)-1,2-ethanediamainebis(trifluoroactate);

[0066]N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N-(trifluoromethylcarbonyl)-1,2-ethanediaminebis(trifluoroacetate);

[0067] Bis(6-chloro-2-methoxy-9-acridinyl)- 1,3-propane;

[0068] Bis(2-methoxy-9-acridinyl)- 1,4-butane bis(trifluoroactate);

[0069]1-(6-chloro-2-methoxy-9-acridinyl)-4-(2-methoxy-9-acridinyl)butane;

[0070] N-(9-acridinyl)-N-(6-chloro-2-methoxy-9-acridinyl)- 1,2-ethanediamine bis(trifluoroactate); and

[0071] N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N,N′-bis(acetyl)-1,2-ethanediamine.

[0072] A preferred group of compounds falling within the scope offormula (I) are compounds of formula (IA) or pharmaceutically acceptablesalts thereof:

[0073] wherein:

[0074] X₁, X₂, X₃ and X₄ are independently H, optionally substitutedC₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄alkyl, CH₂NR′₂, CH₂OR′, CN,COR′, CONR′₂, CO₂R′, CF₃, N(R′)₂, NR′COR′, NR′CONR′R′, NR′CO₂R″,NR′SO₂R″, NO₂, OR′, S(O)₀₋₂R″, S(O)₀₋₂CF₃, or halo;

[0075] R′ is H, optionally substituted C₁₋₆alkyl,C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl;

[0076] R″ is C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl;

[0077] R₁ are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl,Ar-C₀₋₄alkyl, —C(O)CF₃, —C(O)R′, or —SO₂R″, or, the two R₁ groups takentogether may be (C(R)₂)₂₋₃ to form a heterocyclic ring of five to ninemembers;

[0078] n is 0, 1, 2 or 3; and

[0079] R are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl orAr-C₀₋₄alkyl, or, any two R taken together may be (C(R)₂)₂₋₄ to form acarbocyclic ring of three to eight members,

[0080] provided that when n is 1, 2 or 3, R₁ are both H, and R are allH, X₁, X₂, X₃ and X₄ are not all hydrogen; and, provided that when n is1, R₁ are both H, and one of R is CH₃, X₁, X₂, X₃ and X₄ are not allhydrogen; and, provided that when n is 1, R₁ are both H, R are all H,and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4-ethyl,3-methoxy or 4-butoxy; and, provided that when n is 1, and R₁ are bothH, X₁, X₂, X₃ and X4 are not 2-methoxy-6-chloro; and, provided that whenthe two R₁ groups taken together are (CH₂)₂ and form a 6-memberedheterocyclic ring, and R are all H, X₁, X₂, X₃ and X₄ are not2-methoxy-6-chloro; and, provided that when n is 1, R₁ are both H, two Rare (CH₂)₄ to form a six-membered carbocyclic ring, and all other R areH, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and, provided that whenn is 2, R₁ are both H, R are all H, and X₂ and X₃ are each hydrogen, X₁and X₄ are not each 1-NO₂; and, provided that when n is 2, R₁ are bothH, and R are all H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro or2-fluoro-6-chloro; and, provided that when [C(R)₂)_(n)C(R)₂ isCH₂C(CH₃)₂CH₂, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and,provided that when n is 3, R₁ are both H, R are all H, and X₂ and X₃ areeach hydrogen, X₁ and X₄ are not each 4-ethyl, 1-nitro, 3-methoxy, or4-propoxy; and, provided that when n is 3, R₁ are both H, and R are allH, X₁, X₂, X₃ and X₄ are not 3,6-dichloro or 2-methoxy-6-chloro.

[0081] A further preferred group of compounds are those compounds belowfalling within the scope of formula (IA) or pharmaceutically acceptablesalts thereof:

[0082] wherein:

[0083] X₁, X₂, X₃ and X₄ are independently H, optionally substitutedC₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄alkyl, CH₂NR′₂, CH₂OR′, CN,COR′, CONR′₂, CO₂R′, CF₃, N(R′)₂, NR′COR′, NR′CONR′R′, NR′CO₂R″,NR′SO₂R″, NO₂, OR′, S(O)₀₋₂R″, S(O)₀₋₂CF₃, or halo;

[0084] R′ is H, optionally substituted C₁₋₆alkyl,C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl;

[0085] R″ is C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl;

[0086] R₁ are independently H, C₁₋₆alkyl, or one of R¹ is —C(O)CF₃:

[0087] n is 0, 1, 2or 3; and

[0088] R is H or C₁₆alkyl,

[0089] provided that when n is 1, 2 or 3, R₁ are both H, and R are allH, X₁, X₂, X₃ and X₄ are not all hydrogen; and, provided that when n is1, R₁ are both H, and one of R is methyl, X₁, X₂, X₃ and X₄ are not allhydrogen; and, provided that when n is 1, R₁ are both H, R are all H,and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4-ethyl,3-methoxy or 4-butoxy; and, provided that when n is 1, R₁ are both H,and R are all H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and,provided that when n is 2, R₁ are both H, R are all H, and X₂ and X₃ areeach hydrogen, X₁ and X₄ are not each 1-NO₂; and, provided that n is 2,R₁ are both H, and R are all H, X₁, X₂, X₃ and X₄ are not2-methoxy-6-chloro or 2-fluoro-6-chloro; and, provided that when[C(R)₂]_(n)C(R)₂ is CH₂C(CH₃)₂CH₂, X₁, X₂, X₃ and X₄ are not2-methoxy-6-chloro; and, provided that when n is 3, R₁ are both H, R areall H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4-ethyl,1-nitro, 3-methoxy, or 4-propoxy; and, provided that when n is 3, R₁ areboth H, and R are all H, X₁, X₂, X₃ and X₄ are not 3,6-dichloro or2-methoxy-6-chloro.

[0090] Yet another preferred group of compounds are those compoundsbelow failing within the scope of formula (IA) or pharmaceuticallyacceptable salts thereof:

[0091] wherein:

[0092] X₁, X₂, X₃ and X₄ are independently one or more of H, OR′, orhalo;

[0093] R is H or optionally substituted C₁₋₆alkyl;

[0094] R₁ is H, C₁₋₆alkyl, or one of R₁ is —CO(CF₃);

[0095] n is 1 or 2; and

[0096] R is H or C₁₋₆alkyl,

[0097] provided that when R₁ are both H, X₁, X₂, X₃ and X₄ are not allhydrogen; and provided that when n is 1, R₁ are both H, and X₂ and X₃are each hydrogen, X₁ and X₄ are not each 4-ethyl, 3-methoxy, 4-butoxy;and, provided that when n is 1, and R₁ are both H, X₁, X₂, X₃ and X₄ arenot 2-methoxy-6-chloro; and, provided that when n is 2, and R₁ are bothH, X₁, X₂, X₃, and X₄ are not 2-methoxy-6-chloro or 2-fluoro-6-chloro.

[0098] An even more preferred group of compounds are those compoundsbelow falling within the scope of formula (IA) or pharmaceuticallyacceptable salts thereof:

[0099] wherein:

[0100] X₁, X₂, X₃ and X₄ are independently one or more of H, OR′, orhalo;

[0101] R is H or C₁₋₆alkyl optionally substituted with N(CH₃)₂ orCO₂C₁₋₆alkyl;

[0102] R₁ is H, CH₃, or one of R₁ is —CO(CF₃);

[0103] n is 1 or 2; and

[0104] R is H,

[0105] provided that when R₁ are both H, X₁, X₂, X₃ and X₄ are not allhydrogen; and, provided that when n is 1, R₁ are both H, and X₂ and X₃are each hydrogen, X₁ and X₄ are not each 4-ethyl, 3-methoxy, 4-butoxyand, provided that when n is 1, and R₁ are both H, X₁, X₂, X₃ and X₄ arenot 2-methoxy-6-chloro; and, provided that when n is 2, and R₁ are bothH, X₁, X₂, X₃, and X₄ are not 2-methoxy-6-chloro or 2-fluoro-6-chloro.

[0106] A particularly preferred group of compounds are those compoundsbelow falling within the scope of formula (IA) or pharmaceuticallyacceptable salts thereof:

[0107] wherein:

[0108] X₁, X₂, X₃ and X₄ are independently one or more of H, OR′, orhalo;

[0109] R′ is H or C₁₋₆alkyl optionally substituted with N(CH₃)₂, orCO₂C₁₋₆alkyl;

[0110] R₁ is H, CH₃, or one of R₁ is —CO(CF₃);

[0111] n is 1 or 2; and

[0112] R is H,

[0113] provided that when R₁ are both H, X₁, X₂, X₃ and X₄ are not allhydrogen; and, provided that when n is 1, R₁ are both H, and X₂ and X₃are each hydrogen, X₁ and X₄ are not each 4-ethyl, 3-methoxy, 4-butoxy;and, provided that when n is 1, and R₁ are both H, X₁, X₂, X₃ and X₄ arenot 2-methoxy-6-chloro; and, provided that when n is 2, and R₁ are bothH, X₁, X₂, X₃, and X₄ are not 2-methoxy-6-chloro or 2-fluoro-6-chloro.

[0114] This invention also includes methods for preparing the novelcompounds of formula (I) as follows.

[0115] Specifically covered is a method for preparing a compound offormula (I), wherein D and D′ are N, and V and V′ are NR¹ whichcomprises:

[0116] a) treating about two equivalents of a compound of formula (II):

[0117] wherein where X¹ is a suitable leaving group, for example chloro,phenoxy, ethoxy, or bromo, with a compound of formula (III):

[0118] b) reacting a compound of formula (II) with a compound of formula(III) to provide a compound of formula (IV):

[0119] and then reacting the compound of formula (IV) with the same ofdifferent compound of formula (II); or

[0120] c) (i) reacting a compound of formula (II) with a compound offormula (V):

[0121] wherein R² is a suitable protecting group, for example benzyl orbenzyloxycarbonyl, to provide a compound of formula (VI):

[0122] (ii) removing protecting group R² to provide a compound offormula (IV); and

[0123] (iii) reacting the compound of formula (IV) with a compound offormula (II) to provide a compound of formula (I), wherein X, R, n andR¹ are as defined above for formula (I).

[0124] It will be understood that preferred compounds of formula (IA)may be made by analogous processes by varying the substituents on thestaring materials.

[0125] Formulation of Pharmaceutical Compositions

[0126] The pharmaceutically effective compounds of this invention (andthe pharmaceutically acceptable salts thereof) are administered inconventional dosage forms prepared by combining a compound of formula(I) (“active ingredient”) in an amount sufficient to treat asthma andatopic disorders (for example, atopic dermatitis and allergies),rheumatoid arthritis, atherosclerosis, psoriasis, autonimmune diseasessuch as multiple sclerosis, inflammatory bowel disease, and HIVinfection, with standard pharmaceutical carriers or diluents accordingto conventional procedures well known in the art. These procedures mayinvolve mixing, granulating and compressing or dissolving theingredients as appropriate to the desired preparation.

[0127] The pharmaceutical carrier employed may be, for example, either asolid or liquid. Exemplary of solid carriers are lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like. Similarly, the carrier ordiluent may include time delay material well known to the art, such asglyceryl monostearate or glyceryl distearate alone or with a wax.

[0128] A wide variety of pharmaceutical forms can be employed. Thus, ifa solid carrier is used, the preparation can be tableted, placed in ahard gelatin capsule in powder or pellet form or in the form of a trocheor lozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1000 mg. When a liquid carrier isused, the preparation will be in the form of a syrup, emulsion, softgelatin capsule, sterile injectable liquid such as an ampule ornonaqueous liquid suspension.

[0129] The active ingredient may also be administered topically to amanimal in need of treatment of CCR5 mediated disease states. Thus, theactive ingredient may be administered topically in the treatment orprophylaxis of CCR5 mediated disease states, including, but not limitedto, asthma and atopic disorders (for example, atopic dermatitis andallergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmunediseases such as multiple sclerosis, inflammatory bowel disease, and HIVinfection.

[0130] The amount of active ingredient required for therapeutic effecton topical administration will, of course, vary with the compoundchosen, the nature and severity of the disease state being treated andthe mammal undergoing treatment, and is ultimately at the discretion ofthe physician. A suitable dose of an active ingredient is 1.5 mg to 500mg for topical administration, the most preferred dosage being 1 mg to100 mg, for example 5 to 25 mg administered two or three times daily.

[0131] By topical administration is meant non-systemic administrationand includes the application of the active ingredient externally to theepidermis, to the buccal cavity and instillation of such a compound intothe ear, eye and nose, and where the compound does not significantlyenter the blood stream. By systemic administration is meant oral,intravenous, intraperitoneal and intramuscular adrmnistration.

[0132] While it is possible for an active ingredient to be administeredalone as the raw chemical, it is preferable to present it as apharmaceutical formulation. The active ingredient may comprise, fortopical administration, from 0.001% to 10I% w/w, e.g. from 1% to 2% byweight of the formulation although it may comprise as much as 10% w/wbut preferably not in excess of 5% w/w and more preferably from 0.1% to1% w/w of the formulation.

[0133] The topical formulations of the present invention, both forveterinary and for human medical use, comprise an active ingredienttogether with one or more acceptable carrier(s) therefor and optionallyany other therapeutic ingredient(s). The carrier(s) must be acceptablein the sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

[0134] Formulations suitable for topical administration include liquidor semi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose.

[0135] Drops according to the present invention may comprise sterileaqueous or oily solutions or suspensions and may be prepared bydissolving the active ingredient in a suitable aqueous or alcoholicsolution of a bactericidal and/or fungicidal agent and/or any othersuitable preservative, and preferably including a surface active agent.The resulting solution may then be clarified by filtration, transferredto a suitable container which is then sealed and sterilized byautoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

[0136] Lotions according to the present invention include those suitablefor application to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

[0137] Creams, ointments or pastes according to the present inventionare semi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy basis. The basis may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives, or a fattyacid such as stearic or oleic acid together with an alcohol such aspropylene glycol. The formulation may incorporate any suitable surfaceactive agent such as an anionic, cationic or non-ionic surfactant suchas esters or polyoxyethylene derivatives thereof. Suspending agents suchas natural gums, . cellulose derivatives or inorganic materials such assilicaceous silicas, and other ingredients such as lanolin, may also beincluded.

[0138] The active ingredient may also be administered by inhalation. By“inhalation” is meant intranasal and oral inhalation administration.Appropriate dosage forms for such administration, such as an aerosolformulation or a metered dose inhaler, may be prepared by conventionaltechniques. The daily dosage amount of the active ingredientadministered by inhalation is from about 0.1 mg to about 100 mg per day,preferably about 1 mg to about 10 mg per day.

[0139] In one aspect, this invention relates to a method of treatingasthma and atopic disorders (for example, atopic dermatitis andallergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmunediseases such as multiple sclerosis, inflammatory bowel disease, and HIVinfection, all in mammals, preferably humans, which comprisesadministering to such mammal an effective amount of a CCR5 receptorligand, in particular, an antagonist as depicted in formula (I).

[0140] By the term “treating” is meant either prophylactic ortherapeutic therapy. Such formula (I) compound can be administered tosuch mammal in a conventional dosage form prepared by combining theformula (I) compound with a conventional pharmaceutically acceptablecarrier or diluent according to known techniques. It will be recognizedby one of skill in the art that the form and character of thepharmaceutically acceptable carrier or diluent is dictated by the amountof active ingredient with which it is to be combined, the route ofadministration and other well-known variables. The formula (I) compoundis administered to a mammal in need of treatment for asthma and atopicdisorders (for example, atopic dermatitis and allergies), rheumatoidarthritis, atherosclerosis, psoriasis, autoimmune diseases such asmultiple sclerosis, inflammatory bowel disease, and HIV infection, in anamount sufficient to decrease symptoms associated with these diseasestates. The route of administration may be oral or parenteral.

[0141] The term parenteral as used herein includes intravenous,intramuscular, subcutaneous, intra-rectal, intravaginal orintraperitoneal administration. The subcutaneous and intramuscular formsof parenteral administration are generally preferred. The dailyparenteral dosage regimen will preferably be from about 30 mg to about300 mg per day of active ingredient. The daily oral dosage regimen willpreferably be from about 100 mg to about 2000 mg per day of activeingredient.

[0142] It will be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a formula (I) compoundwill be determined by the nature and extent of the condition beingtreated, the form, route and site of I administration, and theparticular mamrnal being treated, and that such optimums can bedetermined by conventional techniques. It will also be appreciated byone of skill in the art that the optimal course of treatment, i.e., thenumber of doses of the formula (I) compound given per day for a definednumber of days, can be ascertained by those skilled in the art usingconventional course of treatment determination tests.

[0143] Methods of Preparation

[0144] The compounds of formula (I) can be prepared by art-recognizedprocedures from known or commercially available starting materials. Ifthe starting materials are unavailable from a commercial source, theirsynthesis is described herein, or they can be prepared by proceduresknown in the art.

[0145] Specifically, compounds of formula (I) where D and D′ are N, andV and V′ are NR¹ are prepared according to the general method of Scheme1 from suitably substituted acridines 1-1, where X¹ is a suitableleaving group, for example chloro, phenoxy, ethoxy, or bromo, and X areas defined in Formula (I). Substituted acridines 1-1 are known to theart and may be prepared by methods known to the art, for example, see“The Acridines”, Second Edition, William Clowes and Sons, London, 1966;Acridines, 2nd ed., Acheson, R. M., Ed., Interscience Publishers, NewYork, 1973, Chapter 1; Heterocycles 1977, 6(7) 987-1060; and J. Med.Chem. 1978, 2], 868-874.

[0146] Compound 1-1 is treated with a suitably substituted diamnine,1-2, where n, R, and R¹ are as defined in formula (I); diamines 1-2 areknown to the art and may be prepared by methods known to the art.

[0147] For example, approximately two equivalents of a suitablysubstituted acridine 1-1 is treated with a suitably substituted diamine1-2 in a suitable solvent, for example phenol or1-methyl-2-pyrrolidinone, at a suitable temperature, for example 25-180°C., for a suitable time, for example 1-4 hours, to give 1-4, asdescribed in J. Am. Chem. Soc. 1947, 69, 468; J. Med. Chem. 1978, 21,658-668; and J. Med. Chem. 1978, 21, 868-874.

[0148] Alternatively, 1-4 may be obtained in two steps by reacting 1-1with 1-2 to afford 1-3 which is then reacted with the same or different1-1 to afford 1-4.

[0149] Alternatively, 1-3 may be heated in a suitable solvent, forexample dimethyl sulfoxide, at a suitable temperature, for example 130°C., for a suitable time, for example four days, to afford 1-4.

[0150] Alternatively, using the general method of Scheme 1, one mayreplace 1-2 with 1-2′ in which R² is a suitable protecting group, forexample benzyl or benzyloxycarbonyl. Reaction of 1-1 and 1-2′ affords1-3′; removal of the protecting group R² from 1-3′ using conditionsknown to the art affords 1-3 which is then reacted with 1-1 to afford1-4.

[0151] Compounds of formula (1) where D and D′ are N, V is NR¹, and V′is S, are prepared according to the general method of Scheme 1 exceptreplacing diamine 1-2 with amino-mercaptan 2-2 as shown in Scheme 2.

[0152] Compound 2-1 is treated with a suitably substitutedamino-mercaptan, 2-2, where n, R, and R¹ are as defined in formula (I);amino-mercaptans 2-2 are known to the art and may be prepared by methodsknown to the art.

[0153] For example, approximately two equivalents of 2-1 are heated with2-2 in a suitable solvent, for example phenol, at a suitabletemperature, for example 80° C., for a suitable time, for example 3hours, to afford 2-3 as described in Tetrahedron 1989, 45, 6455-66.

[0154] Compounds of formula (I) where D and D′ are N, and V and V′ areprepared according to the method of Scheme 3 from substituted9-(mercapto)acridines 3-1 where X are as defined in Formula (I).9-(Mercapto)acridines 3-1, which may also exist as their tautomeric10H-acridine-9-thiones, are known to the art and are prepared by methodsknown to the art.

[0155] Compounds 3-1 are reacted with compounds 3-2 where X² areindependently, suitable leaving groups such as chloro, bromo, iodo,mesyloxy, or tosyloxy, and n and R are as defined in formula (I), togive 3-3. Compounds 3-2 are known to the art and are prepared by methodsknown to the art.

[0156] For example, approximately two equivalents of 3-1 is treated with3-2 in a suitable solvent, for example toluene, and a suitable base, forexample 50% aqueous potassium hydroxide, at a suitable temperature, forexample at reflux, for a suitable time, for example 2 hours, to afford3-3, as described in Eur. J. Med. Chem. 1991, 26, 117-9.

[0157] Compounds of formula (I) where D and D′ are CX, and V and V′ areO are prepared by the general method of Scheme 4 from suitablysubstituted 9-(hydroxy)anthracenes 4-1 where X are as defined in formula(I). Substituted 9-(hydroxy)anthracenes 4-1, which may also exist astheir tautorneric anthrones, are known to the art and may be prepared bymethods known to the art.

[0158] Compounds 4-1 are reacted with compounds 4-2 where X² areindependently, suitable leaving groups such as chloro, bromo, iodo,mesyloxy, or tosyloxy, and n and R are as defined in formula (I), togive 4-4. Compounds 4-2 are known to the art and are prepared by methodsknown to the art.

[0159] For example, a suitably substituted 9-(hydroxy)anthracene 4-1 istreated with 4-2 in a suitable solvent, for example dichloromethane, anda suitable base, for example aqueous sodium hydroxide, and a suitablephase transfer agent, for example tetrabutylammonium hydroxide, at asuitable temperature, for example at reflux, for a suitable time, forexample eleven days to afford 4-3. Treatment of 4-3 with the same ordifferent 4-1 using similar conditions affords 4-4 as described in J.Chem. Soc. Perkin Trans. II 1988, 1885-1894.

[0160] Compounds of formula (I) where D and D′ are CX, V is C(R)₂ and V′is O are prepared according to the method of Scheme 5 from suitablysubstituted anthracine 5-1, where X² is a suitable leaving group such ascnloro, bromo, iodo, mesyloxy or tosyloxy, and X, R, and n are asdefined in Formula (I). Substituted anthracines 5-1 are known to the artand may be prepared by methods known to the art.

[0161] Compound 5-1 is treated with a suitably substituted9-(hydroxy)anthracine, 5-2, where X are as defined in Formula (I);9-(hydroxy)anthracines 5-2 are known to the art and may be prepared bymethods known to the art.

[0162] For example, 5-1 and 5-2 are reacted in a suitable solvent, forexample tetrahydrofuran, and a suitable base, for example aqueous sodiumhydroxide, at a suitable temperature, for example at refiux, for asuitable time, for example 4 hours to afford 5-3 as described in J.Chem. Soc. Perkin Trans. II 1988, 1885-1894.

[0163] Compounds of formula (I) where D and D′ are CX, and V and V¹ areCR₂ are prepared according to the method of Scheme 6 from suitablysubstituted dihydro-anthracines 6-1 where X are as defined in formula(I). Substituted anthracines 6-1 are known to the art and may beprepared by methods known to the art.

[0164] Compound 6-1 is treated with a suitably substituted 6-2, where X²are independently, suitable leaving groups, for example chloro, bromo,iodo, mesd oxy or tosyloxy, and ri and R are as defined in Formula (I).Compounds 6-2 are known to the art and may be prepared by methods knownto the art.

[0165] For example, 6-1 is reated in a suitable solvent , fo r exampletetrahydrofuran, with a suitable base, for example n-butyllithium,treated with 6-2, and then with a suitable oxidant, for example2,3-dichloro-5,6-dicyano-1,4-benzoquinone, to afford 6-3 as described inJ. Chem. Soc. Perkin Trans II 1988, 1885-1894.

[0166] Alternatively, 6-3 may be prepared from a suitably substitutedanthrone and a bis-Grignard as described in J. Am. Chem. Soc. 1980, 102,3524-3530.

[0167] Compounds of formula (I) where one or more X is OR′ are alsoprepared according to the general method of Scheme 7. For example, acompound of formula (I) where one or more X is OR″ and R″ is optionallysubstituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl, e.g.,7-1, is reacted with 4 to 10 equivalents of methionine or a suitablesulfur nucleophile in a suitable solvent, for example methanesulfonicacid, at a suitable temperature, for example 85° C., for a suitabletime, for example 4-18 hours, to give a compound of formula (I) whereone of more X is OH, e.g., 7-2.

[0168] Further, for example, 7-2 is treated with a suitable reagentR″X², where R″ is optionally substituted C₁₋₆alkyl,C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl, and X² is a suitable leavinggroup such as chloro, bromo, iodo, mesyloxy, or tosyloxy, in thepresence of a suitable base, for example sodium hydride or potassiumcarbonate, in a suitable solvent, for example dimethylsulfoxide ordimethylformamide, at a suitable temperature, for example 85° C., for asuitable time, for example 4-18 hours, to give compounds of formula (I)where one or more X is OR″, e.g., 7-3. Reagents defined by R″X² areknown to the art or may be prepared by methods known to the art.

[0169] Reagents: (a) methionine, CH₃SO₃H; (b) DMSO, NaH or DMF, K₂CO₃,R″X².

[0170] Compounds of formula (I) where D and D′ are N, V and V′ are NR¹and one or more of R¹ is acyl are prepared by the general method ofScheme 8. For example, 8-1, is reacted with a suitable acylating agent,for example trifluoroacetic anhydride, and a suitable base, for exampletriethylamine, in a suitable solvent, for example dichloromethane, at asuitable temperature, for example 25° C., for a suitable time, forexample, 18 hours, to give 8-2.

[0171] Reagents: (a) (CF₃CO)₂O, Et₃N, CH₂Cl₂.

[0172] Compounds of formula (I) where D and D′ are N, V and V′ are NR¹,and R¹ is optionally substituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl orAr-C₀₋₄alkyl are prepared by the general method of Scheme 9. Forexample, 9-1 is treated with a suitable base, for example sodiumhydride, in a suitable solvent, for example dimethylsulfoxide, and asuitable alkylating agent, for example iodomethane, at a suitabletemperature, for example 75° C., for a suitable time, for example 1-2hours, to give 9-2.

[0173] Reagents: (a) DMSO, NaH, CH₃I.

[0174] Compounds of formula (I) where D and D′ are N, V and V′ are CH₂,and n is 0 are prepared according to the general method of Scheme 10.For example, 10-1, where X¹ is a suitable leaving group, for examplechloro, phenoxy, ethoxy, or bromo, is converted to malonate 10-2 byreaction with a suitable malonate ester, for example diethyl mnalonate,in the presence of a suitable base, for example sodium ethoxide, in asuitable solvent mixture, for example ethanol and toluene, at a suitabletemperature, for example 85- 100° C., for a suitable time, for example16 hours. The resulting malonate is hydrolyzed in with a suitablereagent, for example hydrochloric acid, at a suitable temperature, forexample 100-120° C., for a suitable time, for example 4 hours to give10-2, using the general method of J. Med. Chem. 1969, 12,913.

[0175] Further, for example, reaction of 10-2 with a suitable aldehyde,for example paraformaldehyde, and a suitable secondary aminehydrochloride, for example dimethylamine hydrochloride, in a suitablesolvent, for example ethanol, at a suitable temperature, for example75-85° C., for a suitable time, for example 2 hours gives compounds offormula 10-3, using the general procedure of Bull. Chem. Soc. Japan,1972, 45, 3187.

[0176] Reagents: (a) diethyl malonate/Na/EtOH; () conc. HCl/H₂O; (c)paraformaldehyde/dimethylamine HCl.

[0177] Compounds of formula (I) where D and D′ are N, V and V′ areC(R)₂, R is H, and n is 2 are prepared according to the general methodof Scheme 11. For example, compounds 11-1, where X¹ is a suitableleaving group, for example chloro, phenoxy, ethoxy, or bromo, aretreated with a suitable alkynol, for example 2-methyl-3-butyn-2-ol, inthe presence of a suitable palladium catalyst, for examplebis(triphenylphosphine)palladium dichloride, in a suitable solventmixture, for example triethylarmine and dimethylformamide, at a suitabletemperature, for example 90° C., for a suitable time, for example 18hours to give an intermediate alkynol. The alkynol is heated to refluxin the presence of a suitable base, for example solid NaOH, in asuitable solvent, for example toluene, at a suitable temperature, forexample 120-150° C., for a suitable time, for example 2 hours, to give11-2 using the general procedure of J. Het. Chem., 1984, 21, 607.

[0178] Compounds 11-2 are treated with a suitable palladium catalyst,for example bis(triphenylphosphine)palladium dichloride, Cul, and asuitable oxidant, for example I₂, in a suitable solvent mixture, forexample diisopropylamnine and dimethylformamide, at a suitabletemperature, for example 25° C., for a suitable time, for example 2hours. The resulting diyne 11-3 is hydrogenated in an atmosphere ofhydrogen gas in the presence of a suitable catalyst, for example 10%palladium on carbon, in a suitable solvent mixture, for example ethylacetate and methanol, at a suitable temperature, for example 25° C., fora suitable time, for example 18 hours, to give 11-4 using the generalmethod of Tet. Lett., 1997, 4371.

[0179] Reagents: (a) 2-methyl-3-butyn-2-W/Pd(PPh₃)₂Cl₂/DMF/TEA; (b)NaOH/toluene;

[0180] (c) Pd(PPh₃)₂Cl₂/CuI/I₂/DMF/i-propylamine, (d) H₂, 10% Pd/C,MeOH, EtOAc.

[0181] Experimentals

EXAMPLE 1

[0182] Preparation ofN,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediaminebis(trifluoroactate)

[0183] N-(6-Chloro-2-methoxy-9-acridinyl)-1,2-ethanediamine (250 mg)(Tetrahedron Lett. 1995, 36, 66514) was dissolved in DMSO and heated to130° C. for 4 d. The mixture was diluted with ethyl acetate and washedwith water. The resulting precipitate was filtered, dried, and purifiedby MPLC (YMC ODS-AQ, 20% acetonitrile/water-0.1% trifluoroacetic acid)to afford the title compound. MS(ES) mle 543.1(M+H)⁺; mp 220-225° C.(decomposition).

EXAMPLE 2

[0184] Preparation ofN,N′-bis(6-chloro-2-methoxv-9-acridinyl)-1,2-ethanediaminebis(trifluoroactate)

[0185] A mixture of 6,9-dichloro-2-methoxyacridine (7 g, 25.3 mmol),ethylenediamine (0.8 mL, 12.6 mmol), and triethylamine (3.5 mL, 25.3mmol) in 1-methyl-2-pyrrolidinone (35 mL) was heated at 130° C. for 2 h.The resulting suspension was filtered to give the title compound, whichwas triturated in hot ethanol and dried (3.8 g). MS(ES) m/e 543.1(M+H)⁺.

EXAMPLE 3

[0186] Preparation of N,N′-di-9-acridinyl-1,2-ethanediaminebis(trifluoroacetate)

[0187] 9-Chloroacridine (1 g, 4.68 mmol), ethylenediamine (0.16 mL, 2.34rnmol), and diisopropylethylamine (1.63 mnL, 9.36 rnmol) in phenol (5 g)were stirred at 115° C. for 3 h. The reaction was cooled andconcentrated hydrochloric acid (4 niL) was added followed by ether (10mL). The resulting precipitate was filtered, triturated with 30% aqueoussodium hydroxide (10 mL), filtered again, washed with water, and driedunder vacuum at 50° C. overnight. A portion of the resulting solid waspurified by MPLC (YMC ODS-AQ, 20% acetonitrile/water-0.1%trifluoroacetic acid) and a portion of the resulting solid was furtherpurified by HPLC (YMC ODS-AQ, 100×250 mm, 80 mLrniin, gradient,A:acetonitrile B:water-0. 1% trifluoroacetic acid, 10-50% during 20 min,UV detection at 254 nm) to give the desired compound as a yellow solid.MS (ES) mile 415.3(M+H)⁺; mp 225-230° C. (decomposition).

EXAMPLE 4

[0188] Preparation ofN,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,3-propanediaminebis(trifluoroactate)

[0189] A mixture of 6,9-dichloro-2-methoxyacridine (0.56 g, 2 mmol),1,3-diamninopropane (0.08 ML, 1 mmol), and triethylamine (0.28 mL, 1mmol) in 1-methyl-2-pyrrolidinone (5 mL) was heated at 130° C. for 2 h.The resulting solid was filtered and purified by HPLC (YMC ODS-AQ,100×250 mm, 80 rnL/min, 20% acetonitrile/water-0.1% trifluoroaceticacid, UV detection at 254 nm) to give the title compound as a yellowsolid. MS(ES) m/e 557.2 (M+H)⁺.

EXAMPLE 5

[0190] Preparation of9,9′-(1,4-piperazinedivl)bis[6-chloro-2-methoxy-acridine]bis(trifluoroacetate)

[0191] A mixture of 6,9-dichloro-2-methoxyacridine (0.56 g, 2 rnrnol),piperazine (0.086 g, 1 rnmol), and triethylamine (0.28 rnL, 1 mnmol) in1-methyl-2-pyrrolidinone (5 mL) was heated at 130° C. for 2 h. Theresulting solid was triturated with a mixture of acetic acid andtrifluoroacetic acid to give the title compound as a yellow solid.MS(ES) m/e 569.1 (M+H)⁺.

EXAMPLE 6

[0192] Preparation ofN-(6-chloro-2-methoxv-9-acridinvl)-N-(6-chloro-2-hvdroxy-9-acridinyl]-1,2-ethanediaminebis(trifluoroacetate)

[0193] A mixture of N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediarnine (0.54 g, 1.0 mmol) and DL-methionine (1.2 g, 8.0nrnol) in methanesulfonic acid (8.0 mL) was heated at 85° C. for 16 h.The reaction was cooled and basified with cold anrnonium hydroxide to pH7.5. The resulting red solid was filtered and purified by HPLC(YMCODS-AQ, 100×250 mm, 80 mL/min, 28% acetonitrilelwater-0.1%trifluoroacetic acid, UV detection at 254 nm) and a portion of theresulting solid was further purified by HPLC to give the title compoundas a yellow solid. MS(ES) m/e 529.3 (M+H)⁺.

EXAMPLE 7

[0194] Preparation ofN,N′-bis(6-chloro-2-hydroxv-9-acridinvl)-1,2-ethanediaminebis(trifluoroactate)

[0195] A mixture of N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1,2-ethanediamine (0.54 g, 1.0 mmol) and DL-methionine (1.48 g, 10.0 m-mol) in methanesulfonic acid (8.0 rnL) was heated at 85° C. for 16 h.The reaction was cooled and basified with cold armmonium hydroxide to pH7.5. The resulting red solid was filtered and purified by HPLC(YMCODS-AQ, 100×250 mm, 80 mL/min, 28% acetonitrile/water-0.1%trifluoroacetic acid, UV detection at 254 nm) and a portion of theresulting solid was further purified by HPLC to give the title compoundas-a yellow solid. MS(ES) m/e 515.2 (M+H)⁺.

EXAMPLE 8

[0196] Preparation ofN-[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyl]-N′-(6-chloro-2-hydroxy-9-acridinvl]-1,2-ethanediaminebis(trifluoroactate)

[0197] To a solution of DMSO (4 mL) and NaH (44 mg, 1.1 mmol) heated at70° C for 15 min was added N,N′-bis(6-chloro-2-hydroxy-9-acridinyl)- 1,2-ethanediamine (0.258 g, 0.5 mmol) and neopentyl iodide (0.22 g, 1.10mmol). After 24 h, the reaction mixture was poured into ice water. Theresulting solid was filtered and purified by HPLC (YMC ODS-AQ, 100×250mm, 80 mL/min. 42% acetonitrile/waterlO.1% trifluoroacetic acid, UVdetection at 254 nm) to give the title compound as a yellow solid. MSES)mnle 585.2 (M+H)⁺.

EXAMPLE 9

[0198] Preparation ofN-[6-chloro-2-(2.2-dimethvlpropoxv)-9-acridinyl]1-N′-(6-chloro-2-methoxy-9-acridinyl]-1,2-ethanediaminebis(trifluoroactate)

[0199] A mixture ofN-(6-chloro-2-methoxy-9-acridinyl)-N′-(6-chloro-2-hydroxy-9-acridinyl-1,2-ethanediamine(0.257 g, 0.5 mmol) and neopentyl iodide (0.22 g, 1.10 mmnol) in DMF (10mL) was heated at 90° C. for 24 h. The reaction mixture was cooled andpoured into ice water. The resulting solid was filtered and purified byHPLC (YMC ODS-AQ, 100×250 mm, 80 mL/min, 48% acetonitrile/water/0.1%trifluoroacetic acid, UV detection at 254 nm) to give the title compoundas a yellow solid. MS(ES) m/e 599.2 (M+H)⁺.

EXAMPLE 10

[0200] Preparation ofN,N′-bis[6-chloro-2-(2.2-dimethvlpropoxy)-9-acridinyl]-1,2-ethanediamine bis(trifluoroactate)

[0201] A mixture of N,N′-bis(6-chloro-2-hydroxy-9-acridin),l)-1,2-ethanediamine (0.258 g, 0.5 mmol), K₂CO₃ (0.56 g, 4 mmol), andneopentyl iodide (0.8 g, 4.0 immol) in DMF (10 mL) was heated at 90° C.for 24 h. The reaction mixture was cooled and poured into ice water. Theresulting solid was filtered and purified by HPLC (YMC ODS-AQ, 100×250mm, 80 mL/min, 50% acetonitrile/water/0.1% trifluoroacetic acid, UVdetection at 254 nm) to give the title compound as a yellow solid.MS(ES) mle 655.3 (M+H)⁺.

EXAMPLE 11

[0202] Preparation ofN,N′-bis[6-chloro-2-(tert-butoxycarbonvl)methoxv-9-acridinvl]-1,2-ethanediaminebis(trifluoroactate)

[0203] To a solution of DMSO (4 mL) and NaH (22 mg, 1.1 mmol) heated at70° C. for 15 min was addedN,N′-bis(6-chloro-2-hydroxy-9-acridinyl)-1,2-ethanediamine (0.129 g, 0.5mnmol) ) and tert-butyl bromoacetate (0.13 g, 0.67 mmol). After 18 h,the reaction mixture was poured into ice water. The resulting solid wasfiltered and purified by HPLC (YMC ODS-AQ, 100×250 mm, 80 mL/min, 39%acetonitrile/water/0.1% trifluoroacetic acid, UV detection at 254 nm) togive the title compound as a yellow solid. MS(ES) mle 743.4 (M+H)⁺.

EXAMPLE 12

[0204] Preparation ofN-[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyl]-N′-[(6-chloro-2-hydroxy-9-acridiny1)-1,2-ethanediamine bis(trifluoroactate)

[0205] To a solution of DMSO (4 mL) and NaH (22 mg, 1.1 rmrmol) heatedat 70° C. for 15 min was addedN,N′-bis(6-chloro-2-hydroxy-9-acridinyl)-1,2-ethanediamine (0.129 g, 0.5imol) and tert butyl bromoacetate (0.13 g, 0.67 mmol). After 18 h, thereaction mixture was poured into ice water. The resulting solid wasfiltered and purified by HPLC (YMC ODS-AQ, 100×250 mm, 80 mL/min, 39%acetonitrile/water/0.1 % trifiuoroacetic acid, UV detection at 254 nm)to give the title compound as a yellow solid. MS(ES) m/e 629.4 (M+H)⁺.

EXAMPLE 13

[0206] Preparation ofN-[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinvl]-N′-(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediaminebis(trifluoroactate)

[0207] To a solution of DMSO (4 rL) and NaH (22 mg, 1.1 rnmol) heated at70° C. for 15 min was added ofN-(6-chloro-2-methoxy-9-acridinyl)-N′-(6-chloro-2-hydroxy-9-acridinyl]-1,2-ethanediamine(0.3 g, 0.6 mmol) and tert-butyl bromoacetate (0.15 g, 0.76 mmol). After8 h, the reaction mixture was poured into ice water. The resulting solidwas filtered and purified by HPLC (YMC ODS-AQ, 100×250 mm, 80 mL/min,38% acetonitrile/water/0.1% trifluoroacetic acid, UV detection at 254nm) to give the title compound as a yellow solid. MS(ES) mle 643.4(M+H)⁺.

EXAMPLE 14

[0208] Preparation ofN,N′-bis(6-chloro-2-carboxymethoxy-9-acridinyl)-1,2-ethanediaminebis(trifluoroactate)

[0209] A solution ofN,N′-bis[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyl]-1,2-ethanediamine(12 mg, 0.12 mmol) and trifluoroacetic acid (5 mL) in dichloromethane(12 mL) was stirred at RT for 18 h. The reaction mixture wasconcentrated in vacuo and the residue was purified by HPLC (YMC ODS-AQ,100×250 mm, 80 niLmin, 26% acetonitrile/water/0.1% trifluoroacetic acid,UV detection at 254 nm) to give the title compound as a yellow solid.MS(ES) m/e 631.3 (M+H)⁺.

EXAMPLE 15

[0210] Preparation ofN-[6-chloro-2-(2-dimethylamino)ethoxv-9-acridinvll-N′-(6-chloro-2-hvdroxy-9-acridinyl]-1,2-ethanediaminebis(trifluoroactate)

[0211] To a solution of DMSO (4 mL) and NaH (22 mg, 1.1 Immol) heated at70° C for 15 min was added N,N′-bis(6-chloro-2-hydroxy-9-acridinyl)- 1,2-ethanediamine (0.258 g, 0.5 mmol) and 2-(dimethylamino)ethyl chloride(0.317.g, 2.2 nimol). After 18 h, the reaction mixture was poured intoice water. The resulting solid was filtered and purified by HPLC (YMCODS-AQ, 100×250 mm, 80 mL/min, 26% acetonitrile/water/0.1%trifluoroacetic acid, UV detection at 254 nm) to give the title compoundas a yellow solid. MS(ES) m/e 586.3 (M+H)⁺.

EXAMPLE 16

[0212] Preparation ofN,N′-bis[(6-chloro-2-methoxy-9-acridinyl]-N,N′-dimethyl-1,2-ethanediaminebis(trifluoroactate)

[0213] To a solution of DMSO (4 mL) and NaH (40 mg, 1.0 mmol) heated at70° C. for 15 min was added N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1,2-ethanediamine (0.27 g, 0.5 inmol) followed by methyl iodide (0.06niL, 1.0 rimol). After 1 h, the reaction mixture was poured into icewater. The resulting solid was filtered and purified by HPLC (YMCODS-AQ, 100×250 mm, 80 ml/min, 35% acetonitrile/water/0.1%trifluoroacetic acid, UV detection at 254 nm) to give the title compoundas a yellow solid. MS(ES) m/e 571.2 (M+H)⁺.

EXAMPLE 17

[0214] Preparation ofN,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N-(trifluoromethylcarbonyl)-1,2-ethanediaminebis(trifluoroactatel

[0215] To a suspension ofN,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediarnine (0.27 g, 0.5rnmol) in dichloromethane (20 mL) was added triethyl amine (1 mL, 7mnmol) followed by trifluoroacetic anhydride (1 mL, 7.0 mmol). After18h, the solution was diluted with dichloromethane (100 nIL), washedwith water, dried and concentrated in vacuo to a yellow semi-solid,which was purifiefd by HPLC (YMC ODS-AQ, 100 x 250 mm, 80 mL/min, 50%acetonitrile/waterlO. 1% trifluoroacetic acid, UV detection at 254 nm)to give the titled compound as a yellow solid. MS(ES) rnle 639.1 (M+H)⁺.

EXAMPLE 18

[0216] Preparation ofN,N′-bis(6-chloro-2-methoxy-9-acridinvl)-N,N′-bis(trifluoromethylcarbonyl)-1,2-ethanediaminebis(trifluoroactate)

[0217] To a suspension of N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediamine (0.157 g, 0.3 mrol) in dichloromethane (10 mL) wasadded triethylamine (3 mL, 20 mmol) followed by trifluoroaceticanhydride (3 mnL, 20 mmol). After 18h, the solution was diluted withdichloromethane (100 mL), washed with water, dried and concentrated invacuo to give yellow solid, which was purified by flash columnchromatography (silica gel, 1-2 % methanol:dichloromethane) to give thetitle compound as a yellow solid. MS(ES) m/e 735.3 (M+H)⁺.

EXAMPLE 19

[0218] Preparation of bis(6-chloro-2-methoxy-9-acridinyl)-1,3-propane

[0219] a) diethyl (6-chloro-2-methoxv-9-acridinyl)malonate

[0220] To a solution of sodium (1.3 g, 52 mmol) in ethanol (50 mnL) wasadded diethyl malonate (8.8 g 55 mmol) followed by6,9-dichloro-2-methoxyacridine (9.68 g, 35 mmol) and toluene (5 mL). Themixture was heated to reflux for 24 h, diluted with aqueous potassiumcarbonate, extracted with ethyl acetate, dried, and concentrated invacuo to give solid which was purified by flash column chromatography(silica gel, 5-12% methanol:dichloromethane) to give the title compound.MS(ES) m/e 402.2 (M+H)⁺.

[0221] b) 6-chloro-2-methoxy-9-methylacridine

[0222] A solution of the compound of Example 19 (a) (2.2 g, 5.5 mmol) inwater (5 mL) and concentrated hydrochloric acid was heated to reflux for4 h and filtered to give the title compound. MS(ES) mn/e 258.2 (M+H)⁺.

[0223] c) bis(6-chloro-2-methoxy-9-acridinyl)-1,3-propane

[0224] A mixture of the compound of Example 19 (b) (0.32 g, 1.1 Immol),paraformaldehyde (40 mg), and dimethylarnine hydrochloride (0.14 g, 1.7rnmol) in ethanol (4 mL) was heated at 80° for 2.5 h. The suspension wascooled and filtered to give the title compound. MS(ES) m/e 527.3 (M+H)⁺.

EXAMPLE 20-21

[0225] Preparation of bis(2-methoxy-9-acridinyl)-1,4-butane and1-(6-chloro-2-methoxy-9-acridinyl)-4-(2-methoxy-9-acridinyl)butane

[0226] a) 2-methyl4-(6-chloro-2-methoxy-9-acridinyl)-3-butyn-2-ol

[0227] A mixture of 6,9-dichloro-2-methoxyacridine (3.5 g, 12.6 mmol),2-methyl-3-butyn-2-ol (1.27 g, 15 nmmol),dichlorobis(triphenylphosphine)palladium (100 mg), and cuprous iodide(25 mg) in triethylarine (35 mL) and dimethylformamide (20 mL) washeated at 90° for 12 h. The mixture was cooled and diluted with aqueouspotassium carbonate to give the title compound. MS(ES) mle 326.2 (M+H)⁺.

[0228] b) 9-ethynyl-6-chloro-2-methoxyacridine

[0229] A solution of the compound of Example 20 (a) (2 g, 6.15 mmnol)and sodium hydroxide (0.25 g, 6.25 mmol) in toluene (100 rnL) was heatedto reflux for 5 h. The mixture was concentrated and residue was taken upin dichloromethane, washed with water, dried, and concentrated in vacuoto give the title compound. MS(ES) m/e 268.1 (M+H)⁺.

[0230] c) bis(2-methoxy-9-acridinyl)-1,4-butadiyne

[0231] A mixture of the compound of Example 20 (b) (0.272 g, I mmol),dichlorobis(triphenylphosphine)palladium(100 mg), cuprous iodide (25mg), and iodine (0.128 g, 0.5 mmol) in diethylamine (6 mL) anddimethylformamide (3 mL) was stirred for 2 h and filtered to give thetitle compound.

[0232] d) bis(2-methoxy-9-acridinyl)- 1,4-butane and1-(6-chloro-2-methoxy-9-acridinyl)-4-(2-methoxy-9-acridinvy)butane

[0233] A mixture of the compound of Example 20(c) and 10%palladium-on-carbon (0.12 g) in methanol (25 mL) and ethyl acetate (25mL) was stirred in an atmosphere of hydrogen. After 18 h, the mixturewas filtered and the filtrate was concentrated in vacuo and the residuewas purified by HPLC (YMC ODS-AQ, 100×250 mm, 80 mL/min, 30%acetonitrile/waterlO. 1 % trifluoroacetic acid, UV detection at 254 nm)to give the title compounds. MS(ES) m/e 473.3 (M+H)+and 527.3 (M+H)⁺,respectively.

EXAMPLE 22

[0234] Preparation ofN-(9-acridinyl)-N′-(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediaminebis(trifluoroacetate)

[0235] A mixture ofN-(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediaamine (0.4 g, 1.3 mmol)and 9-chloroacridine (0.28 g, 1.3 mmol), was heated at 130° C. for 1min. The resulting suspension was cooled and filtered. The filtate waspurified by. HPLC (YMC ODS-AQ, 100×250 mm, 80 mL/min, 20%acetonitrilelwater-0.1% trifluoroacetic acid, UV detection at 254 nm) togive the title compound as a yellow solid. MS(ES) m/e 479.3 (M+H)⁺.

EXAMPLE 23

[0236] Preparation ofN,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N,N′-bis(acetyl)-1,2-ethanediamine

[0237] To a suspension ofN,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediamine (0.157 g, 0.3mmol) in dichloromethane (10 mL) was added triethylamine (4.5 mL, 32mmol) followed by acetic anhydride (3 mnL, 32 mmol). After 18h, thesolution was diluted with dichloromethane (100 mnL), washed with water,dried and concentrated in vacuo to give yellow solid, which was purifiedby flash column chromatography (silica gel, 1% methanol:dichloromethane)to give the title compound as a yellow solid. MS(ES) m/e 627.3 (M+H)⁺.

[0238] Biological Data:

[0239] CCR5 Receptor Binding Assay:

[0240] CHO cell membranes (0.25×10⁶ cell equivalents) derived from CHOcells stably transfected with CCR5 were incubated with 0.3¹²⁵I-RANTES ina 96 well plate for 45 min at room temperature (final reaction volume200 μl). The reaction was terminated by filtration and the filters(GF/C) were washed twelve times with a solution of phosphate bufferedsaline containing 0.1% bovine serum albumin and 0.05% NaN₃. Theradioactivity bound to filters was measured by liquid scintillationspectrometry. Non-specific binding was determined in the presence ofunlabelled RANTES (10 or 30 nNM) and averages 30-50% of total binding.

[0241] CCR5 Receptor Functional Assay:

[0242] The cellular functional assay used to assess antagonist activityof compounds was RANTES-induced Ca²⁺ mobilization in RBL 2H3 cellsstably expressing the hCCR5 receptor (RBL 2H3 hCCR5). Cells were grownto 80-100% confluency in T-150 flasks and washed with phosphate-bufferedsaline. Cells were lifted from the flasks by treating with 3 mL of 1 mMEDTA for 3 min at room temperature and diluting to 2×10⁶ cellslmL withKrebs Ringer Henseleit buffer (KRH; 118 mM NaCl, 4.6 mM KCl, 25 mMNaHCO₃, 1 mM KH₂PO₄ and 11 mM glucose) containing 5 mM HEPES (pH 7.4), 1mM CaCI₂, 1 mM MgCl₂ and 0.1% BSA and centrifuged at 200 g for 3 min.Cells were resuspended at 2×10⁶ cells/mL in the same buffer with 2 μMFura-2AM, and incubated for 35 min at 37° C. Cells were centrifuged at200× g for 3 min and resuspended in the same buffer without Fura-2AM,then incubated for 15 min at 37° C. to complete the hydrolysis ofintracellular Fura-2AM, and then centrifuged as before. Cells (10⁶cells/mL) were resuspended in cold KRH with 5 mM HEPES (pH 7.4), 1 mMCaCl₂, 1 mM MgCI₂ and 0.1% gelatin and maintained on ice until assayed.For antagonist studies, aliquots (2 mL) of cells were prewarmed at 37°C. for 5 min in 3 mL plastic cuvettes and fluorescence measured in afluorometer (Johnson Foundation Biomedical Group, Philadelphia, Pa.,USA) with magnetic stirring and temperature maintained at 37° C.Excitation was set at 340 nm and emission set at 510 nm. Variousconcentrations of antagonists or vehicle were added and fluorescencemonitored for ˜15 sec to ensure that there was no change in baselinefluorescence, followed by the addition of 33 nM RANTES. Maximal Ca²⁺attained after 33 nM RANTES stimulation was calculated as described byGrynkiewicz et al., (1985). The percent of maximal RANTES-induced Ca²⁺was determined for each concentration of antagonist and the IC₅₀,defined as the concentration of test compound that inhibits 50% of themaximal 33 nM RANTES response, obtained from the concentration-responsecurves (5-7 concentrations of antagonists).

[0243] The compounds of this invention show CCR5 receptor antagonistactivity having IC₅₀ values in the range of 0.0001 to 100 μM. The fullstructure/activity relationship has not yet been established for thecompounds of this invention. 20 However, given the disclosure herein,one of ordinary skill in the art can utilize the present assays in orderto determine which compounds of formula (I) are ligands of the CCR5receptor and which bind thereto with an IC₅₀ value in the range of0.0001 to 100 μM.

[0244] All publications, including, but not limited to, patents andpatent applications cited in this specification, are herein incorporatedby reference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

[0245] The above description fully discloses the invention includingpreferred embodiments thereof. Modifications and improvements of theembodiments specifically disclosed herein are within the scope of thefollowing claims. Without further elaboration it is believed that oneskilled in the art can, given the preceding description, utilize thepresent invention to its fullest extent. Therefore any examples are tobe construed as merely illustrative and not a limitation on the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A method of treating a CCR5-mediated disease state in mammals which comprises administering to a mammal in need of such treatment, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein: X are independently one or more of H, optionally substituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alky, Ar-C₀₋₄alkyl, CH₂NR′₂, CH₂OR′, CN, COR′, CONR′₂, CO₂R′, CF₃, NR′₂, NR′COR′, NR′CONR′R′, NR′CO₂R″, NR′SO₂R″, NO₂, OR′, S(O)₀₋₂R″, S(O)₀₋₂CF₃, or halo; R′ is H, optionally substituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkiyl or Ar-C₀₋₄alkyl; R″ is C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl; D and D′ are independently CX or N; V and V′ are independently C(R)₂, NR¹, O, or S(O)₀₋₂; R¹ are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄alkyl, —C(O)CF₃, —C(O)R′, or —SO₂R″, or, when V and V′ are —NR¹, the two R¹ groups taken together may be (C(R)₂)₂₋₃ to form a heterocyclic ring of five to nine members; n is 0, 1, 2 or 3; and R are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl, or, when V and V′ are independently NR¹, O or S(O)₀₋₂, any two R taken together may be (C(R)₂)₂₋₄ to form a carbocyclic ring of three to eight members.
 2. The method as claimed in claim 1 wherein the compound of formula (I) is a compound selected from: N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1 ,2-ethanediarine bis(trifluoroactate); N,N′-di-9-acridinyl-1,2-ethanediamine bis(trifluoroactate); N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1 ,3-propanedi amine bis(trifluoroactate); 9,9′-(1,4-piperazinediyl)bis-6-chloro-2-methoxy-acridine bis(trifluoroacetate); N-(6-chloro-2-methoxy-9-acridinyl)-N-(6-chloro-2-hydroxy-9-acridinyl)-1,2-ethanediamine bis(trifluoroacetate); N,N′-bis(6-chloro-2-hydroxy-9-acridinyl)- 1 ,2-ethanediamine bis(trifluoroactate); N-[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyll-N-(6-chloro-2-hydroxy-9-acridinyl]-1,2-ethanediamine bis(trifluoroactate); N-[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyl-N-(6-chloro-2-methoxy-9-acridinyl]-1,2-ethanediarnine bis(trifluoroactate); N,N′-bis[6-chloro-2-(2,2-dimethylpropoxy)-9-acridinyl]- 1 ,2-ethanediamine bis(trifluoroactate); N,N′-Bis[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyl]-1,2-ethanediamine bis(trifluoroactate); N-[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyll-N-(6-chloro-2-hydroxy-9-acridinyl)-1,2-ethanediamine bis(trifluoroactate); N-[6-chloro-2-(tert-butoxycarbonyIl)methoxy-9-acridinyl]-N-.(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediamnine bis(trifluoroactate); N,N′-bis(6-chloro-2-carboxymethoxy-9-acridinyl)- 1 ,2-ethanediamine bis(trifluoroactate); N-[6-chloro-2-(2-dimethylamino)ethoxy-9-acridinyll-N-(6-chloro-2-hydroxy-9-acridinyl]- 1.2-ethanediamnine bis(trifluoroactate); N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N,N′-dimethyl- 1,2-ethanediamine bis(trifluoroactate); N,N′-bis(6chloro-2-methoxy-9-acridinyl)-N,N′7-bis(trifluoromethylcarbonyl)-1,2-ethanediarrine bis(trifluoroactate); N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N-(trifluoromethylcarbonyl)- 1,2-ethanediamine bis(trifluoroacetate); Bis(6-chloro-2-methoxy-9-acridinyl)- 1,3-propane; Bis(2-methoxy-9-acridinyl)-1,4-butane bis(trifluoroactate); 1-(6-chloro-2-methoxy-9-acridinyl)4-(2-methoxy-9-acridinyl)butane, N-(9-acridinyl)-N-(6-chloro-2-methoxy-9-acridinyl)- l ,2-ethanediamine,. bis(trifluoroactate); and N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-N,N′-bis(acetyl)- 1,2-ethanediamine.
 3. The method as claimed in claim 1 , wherein the disease is selected from asthma and atopic disorders, rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection.
 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein: X are independently one or more of H, optionaly substituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄alkyl, CH₂NR′₂, CH₂OR′, CN, COR′, CONR′₂, CO₂R′, CF₃, N(R′)₂, NR′COR′, NR′CONR′R′, NR′CO₂R″, NR′SO₂R″, NO₂, OR′, S(O)₀₋₂R″, S(O)₀₋₂CF₃, or halo; R′ is H, optionally substituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl; R″ is C₁₋₆alkl, C₃₋₇cycloalkyl-C₀₋₄-alkyl or Ar-C₀₋₄alkyl; D and D′ are independently CX or N; V and V′ are independently C(R)₂, NR₁, O, or S(O)₀₋₂; R₁ are independently H, C₁₋₆alkyl, C₃₋₇cycloalky-C₀₋₄alkyl, Ar-C₀₋₄alkyl, —C(O)CF₃, —C(O)R′, or —SO₂R″, or, when V and V′ are —NR₁, the two R₁ groups taken together may be (C(R)₂)₂₋₃ to form a heterocyclic ring of five to nine members; n is 0, 1, 2or 3; and R are independently H, C₁₋₆alkyl, C₃₋₇cycIoalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl, or, when V and V′ are independently NR¹, O or S(O)₀₋₂, any two R taken together may be (C(R)₂)₂₋₄ to form a carbocyclic ring of three to eight members, with the proviso that the compound of formula (I) is not 9,9′-(1,3-propanediyl)bis-acridine; 9,9′-(1,5-pentanediyl)bis-acridine; N,N′-di-9-acridinyl-1,2-ethanediamine; N,N′-bis(4-ethyl-9-acridinyl)- 1,2-ethanediaamine; N,N′-bis(3-methoxy-9-acridinyl)-1,2-ethanediamine; N,N′-bis(4-butoxy-9-acridinyl)-1,2-ethanediarnine; N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1,2-ethanediamine; trans-N,N′-bis(6-chloro-2-methoxy-9-acridinyl)- 1,2-cyc]ohexanediarnine; 9,9′-(1,4-piperazinediyl)bis[6-chloro-2-methoxy-acridine]; N,N′-di-9-acridinyl-1,2-propanediamine; N,N′-di-9-acridinyl-1,3-propanediamine; N,N′-bis(1-nitro-9-acridinyl)-1,3-propanediamine; N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,3-propanediamine; N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-2,2-methyl-1,3-propanediamine; N,N′-bis(6-chloro-2-fluoro-9-acridinyl)- 1,3-propanediamine; N,N′-di-9-acridinyl-1,4-butanediamine; N,N′-bis(4-ethyl-9-acridinyl)-1,4-butanediamnine; N,N′-bis(1-nitro-9-acridinyl)- 1,4-butanediamine; N,N′-bis(3-methoxy-9-acridinyl)-1,4-butanediamine; N,N′-bis(4-propoxy-9-acridinyl)-1,4-butanediamine; N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,4-butanediamine; N,N′-bis(3,6-dichloro-9-acridinyl)-1,4-butanediamine; 6-chloro-N-[2-[(6-chloro-2-methoxy-9-acridinyl)thio]ethyl]-2-methoxy-9-acridinamine; 9,9′-[1,2-ethanediylbis(thio)]bis-acridine; 9,9′-[1,2-ethanediylbis(thio)]bis-3-acridinamine; 9,9′-[1,3-propanediy]bis(thio)3bis-acridine; 9-[1,4-butanediylbis(thio)]bis-acridine; 9,9′-[1,4-butanediylbis(thio)]bis-1-acridinamine; 9,9′-[1,4-butanediylbis(thio)]bis-3-acridinaniine; 9,9′-[1,4-butanediylbis(thio)]bis4-acridinamine; 9,9′-[methylenebis(oxy)]bis-anthracene; 9-[methylenebis(oxy)]bis[10-methoxy-anthracenel; 9,9′-[methylenebis(oxy)]bis[10-propoxy-anthracene]; 9,9′-[methylenebis(oxy)]bis 10-(2-methoxyethoxy)-anthracene]; 9,9′-[1,2-ethanediylbis(oxy)]bis-anthracene; 9,9′-(1,3-propanediyl)bis-anthracene; 9,9′-(1,4-butanediyl)bis-anthracene; 9,9′-(1,4-butanediyl)bis 10-(chloromethyl)-anthracene; 9-13-(9-anthracenyloxy)propyl)anthracene; 9,9′-(1,5-pentanediyl)bis-anthracene; 9,9′-(1,5-pentanediyl)bis 10-(chloromethyl)-anthracene; and 9,9′-(1,6-hexanediyl)bis-anthracene.
 5. A compound of formula (IA) or a pharmaceutically acceptable salt thereof: wherein: X₁, X₂, X₃ and X₄ are independently H, optionally substituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄alkyl, CH₂NR′₂, CH₂OR′, CN, COR′, CONR′₂, CO₂R′, CF₃, N(R′)₂, NR′COR′, NR′CONR′R′, NR′CO₂R″, NR′SO₂R″, NO₂, OR′, S(O)₀₋₂R″, S(O)₀₋₂CF₃ or halo; R′ is H, optionally substituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl; R″ is C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl; R₁ are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄alkyl, —C(O)CF₃, —C(O)R′, or —SO₂R″, or, the two R₁ groups taken together may be (C(R)₂)₂₋₃ to form a heterocyclic ring of five to nine members; n is 0, 1, 2 or 3; and R are independently H, C₁₋₆alky, C₃₋₇cycloalkyI-C₀₋₄alkyl or Ar-C₀₋₄alkyl, or, any two R taken together may be (C(R)₂)₂₋₄ to form a carbocyclic ring of three to eight members, provided that when n is 1, 2 or 3, R₁ are both H, and R are all H, X₁, X₂, X₃ and X₄ are not all hydrogen; and, provided that when n is 1, R₁ are both H, and one of R is CH₃, X₁, X₂, X₃ and X₄ are not all hydrogen; and, provided that when n is 1, R₁ are both H, R are all H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4-ethyl, 3-methoxy or 4-butoxy; and, provided that when n is 1, and R₁ are both H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and, provided that when the two R₁ groups taken together are (CH₂)₂ and form a 6-membered heterocyclic ring, and R are all H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and, provided that when n is 1, R₁ are both H, two R are (CH₂)₄ to form a six-membered carbocyclic ring, and all other R are H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and, provided that when n is 2, R₁ are both H, R are all H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 1-NO₂; and, provided that when n is2, R₁ are both H, and R are all H, X₁, X₂, X₃ and X₄are not2-methoxy-6-chloro or 2-fluoro-6-chloro; and, provided that when [C(R)₂]_(n)C(R)₂, is CH₂C(CH₃)₂CH₂, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and, provided that when n is 3, R₁ are both H, R are all H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4-ethyl, 1-nitro, 3-methoxy, or 4-propoxy; and, provided that when n is 3, R₁ are both H, and R are all H, X₁, X₂, X₃ and X₄ are not 3,6-dichloro or 2-methoxy-6-chloro.
 6. A compound of formula (IA) or a pharmaceutically acceptable salt thereof:

wherein: X₁, X₂, X₃ and X4 are independently H, optionally substituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Ar-C₀₋₄alkyl, CH₂NR′₂, CH₂OR′, CN, COR′, CONR′₂, CO₂R′, CF₃, N(R′)₂, NR′COR′, NR′CONR′R′, NR′CO₂R″, NR′SO₂R″, NO₂, OR′, S(O)₀₋₂R″, S(O)₀₋₂CF₃, or halo; R′ is H, optionally substituted C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl; R″ is C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar-C₀₋₄alkyl; R₁ are independently H, C₁₋₆alkyl, or one of R₁ is —C(O)CF₃; n is 0, 1, 2 or 3; and R is H or C₁₋₆alkyl, provided that when n is 1, 2 or 3, R₁ are both H, and R are all H, X₁, X₂, X₃ and X₄ are not all hydrogen; and, provided that when n is 1, R₁ are both H, and one of R is methyl, X₁, X₂, X₃ and X₄ are not all hydrogen; and, provided that when n is 1, R₁ are both H, R are all H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4-ethyl, 3-methoxy or 4-butoxy; and, provided that when n is 1, R₁ are both H, and R are all H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and, provided that when n is 2, R₁ are both H, R are all H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 1-NO₂; and, provided that n is 2, R₁ are both H, and R are all H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro or 2-fluoro-6-chloro; and, provided that when [C(R)₂]_(n)C(R)₂ is CH₂C(CH₃)₂CH₂, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and, provided that when n is 3, R₁ are both H, R are all H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4-ethyl, 1-nitro, 3-methoxy, or 4-propoxy; and, provided that when n is 3, R₁ are both H, and R are all H, X₁, X₂, X₃ and X₄ are not 3,6-dichloro or 2-methoxy-6-chloro.
 7. A compound of formula (IA) or a pharmaceutically acceptable salt thereof:

wherein: X₁, X₂, X₃ and X₄ are independently one or more of H, OR′, or halo; R′ is H or optionally substituted C₁₋₆alkyl; R₁ is H, C₁₋₆alkyl, or one of R₁ is —CO(CF₃); n is 1 or 2; and R is H or C₁₋₆alkyl, provided that when R₁ are both H, X₁, X₂, X₃ and X₄ are not all hydrogen; and provided that when n is 1, R₁ are both H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4ethyl, 3-methoxy, 4-butoxy; and, provided that when n is 1, and R₁ are both H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6chloro; and, provided that when n is 2, and R₁ are both H, X₁, X₂, X₃, and X₄ are not 2-methoxy-6-chloro or 2-fluoro-6-chloro.
 8. A compound of formula (IA) or a pharmaceutically acceptable salt thereof:

wherein: X₁, X₂, X₃ and X₄ are independently one or more of H, OR′, or halo; R is H or C₁₋₆alkyl optionally substituted with N(C₁₋₆alkyl)₂, or CO₂C₁₋₆alkyl; R₁ is H, CH₃, or one of R₁ is —CO(CF₃); n is 1 or 2; and R is H, provided that when R₁ are both H, X₁, X₂, X₃ and X₄ are not all hydrogen; and, provided that when n is 1, R₁ are both H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4-ethyl, 3-methoxy, 4-butoxy; and, provided that when n is 1, and R₁ are both H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and, provided that when n is 2, and R₁ are both H, X₁, X₂, X₃, and X₄ are not 2-methoxy-6-chloro or 2-fluoro-6-chloro.
 9. A compound of formula (IA) or a pharmaceutically acceptable salt thereof:

wherein: X₁, X₂, X₃ and X₄ are independently one or more of H, OR, or halo; R′ is H or C₁₋₆alkyl optionally substituted with N(CH₃)₂, or CO₂C₁₋₆alkyl; R₁ is H, CH₃, or one of R₁ is —CO(CF₃); n is 1 or 2; and R is H, provided that when R₁ are both H, X₁, X₂, X₃ and X₄ are not all hydrogen; and, provided that when n is 1, R₁ are both H, and X₂ and X₃ are each hydrogen, X₁ and X₄ are not each 4-ethyl, 3-methoxy, 4-butoxy; and, provided that when n is 1, and R₁ are both H, X₁, X₂, X₃ and X₄ are not 2-methoxy-6-chloro; and, provided that when n is 2, and R₁ are both H, X₁, X₂, X₃, and X₄ are not 2-methoxy-6-chloro or 2-fluoro-6-chloro. 